Context: Glucose-insulin-potassium (GIK) infusion is a widely applicable, low-cost therapy that has been postulated to improve mortality in patients with acute ST-segment elevation myocardial infarction (STEMI). Given the potential global importance of GIK infusion, a large, adequately powered randomized trial is required to determine the effect of GIK on mortality in patients with STEMI. Objective: To determine the effect of high-dose GIK infusion on mortality in patients with STEMI. Design, Setting, and Participants: Randomized controlled trial conducted in 470 centers worldwide among 20201 patients with STEMI who presented within 12 hours of symptom onset. The mean age of patients was 58.6 years, and evidence-based therapies were commonly used. Intervention: Patients were randomly assigned to receive GIK intravenous infusion for 24 hours plus usual care (n = 10091) or to receive usual care alone (controls; n = 10110). Main Outcome Measures: Mortality, cardiac arrest, cardiogenic shock, and reinfarction at 30 days after randomization. Results: At 30 days, 976 control patients (9.7%) and 1004 GIK infusion patients (10.0%) died (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.95-1.13; P=.45). There were no significant differences in the rates of cardiac arrest (1.5% [151/10107] in control and 1.4% [139/10088] in GIK infusion; HR, 0.93; 95% CI, 0.74-1.17; P=.51), cardiogenic shock (6.3% [640/10107] vs 6.6% [667/10088]; HR, 1.05; 95% CI, 0.94-1.17; P=.38), or reinfarction (2.4% [246/10107] vs 2.3% [236/10088]; HR, 0.98; 95% CI, 0.82-1.17; P=.81). The rates of heart failure at 7 days after randomization were also similar between the groups (16.9% [1711/10107] vs 17.1% [1721/ 10088]; HR, 1.01; 95% CI, 0,95-1.08; P=.72). The lack of benefit of GIK infusion on mortality was consistent in prespecified subgroups, including in those with and without diabetes, in those presenting with and without heart failure, in those presenting early and later after symptom onset, and in those receiving and not receiving reperfusion therapy (thrombolysis or primary percutaneous coronary intervention). Conclusion: In this large, international randomized trial, high-dose GIK infusion had a neutral effect on mortality, cardiac arrest, and cardiogenic shock in patients with acute STEMI.